The field of invention is Vibrio cholerae vaccines.
After more than 100 years of research on cholera, there remains a need for an effective cholera vaccine. There have been six pandemics of this disease caused by strains of V. cholera belonging to the "Classical" biotype. The etiological agents of the current (seventh) pandemic belong to the "El Tor" biotype (Finkelstein, Crit. Rev. Microbiol 2:553-623, 1973, Wachsmuth et al., The Lancet 337:1097-1098, 1991). Recently the seventh pandemic has extended to a new locale, that of South America. Beginning in January of 1991, an epidemic of cholera resulted in greater than 250,000 cases and over 2,000 deaths in Peru, Ecuador, Columbia, and Chile. Before this epidemic it was estimated that over 200,000 cases of cholera occurred per year mainly in India, Bangladesh, Africa and Western Asia (Tacket et al., Cholera Vaccines. In Vaccines: New Approaches to Immunological Problems, Ellis, R. W., editor, Butterworth-Heinemann, Boston, 1992).
Because natural infection by and recovery from cholera induces immunity lasting at least 3 years (Tacket et al., Supra; Levine et al., J. Infect. Dis. 143:818-820, 1981; Cash et al., J. Infect. Dis. 130:325-333, 1974), much effort has been made to produce live, attenuated cholera vaccines that when administered orally would mimic the disease in its immunization properties but would not cause adverse symptoms or reactions in the immunized individual (i.e., display low reactogenicity). Vaccines of this type involve deletion mutations that inactivate the gene encoding the A subunit of cholera toxin, a protein which is responsible for most of the diarrhea seen in this disease (Mekalanos et al., Proc. Natl. Acad. Sci. USA 79:151-155, 1982; Mekalanos et al., Nature 306:551-557, 1983; Kaper et al., Nature 308:655-658, 1984; Kaper et al., Biotechnology 2:345, 1984; Pierce et al., Infect. Immun. 55:477-481, 1987; Taylor et al., Vaccine 6:151-154, 1988; Levine et al., Infn. Immun. 56: 161-167, 1988; Herrington et al. J. Exper. Med. 168:1487-1492, 1988; Levine et al., Lancet ii:467-470, 1988; Kaper et al., Res. Microbiol. 141:901-906, 1990; Pearson et al., Res. Microbiol. 141:893-899, 1990). See also Mekalanos, U.S. Pat. Nos. 5,098,998 and 4,882,278, and Kaper et al., U.S. Pat. No. 4,935,364, hereby incorporated by reference. The major issues associated with cholera vaccines are safety, stability and their degree of antigenicity.
With regard to the toxin genes of V. cholerae, the genetic diversity among toxigenic and non-toxigenic strains has been examined by Chen et al. (1991, Epidemiol. Infect. 107:225). Mekalanos (1983, Cell 35:253) reports on the duplication and amplification of V. cholerae toxin genes, and Miller et al. (1984, Proc. Natl. Acad. Sci. USA 81:3471) discusses transcriptional regulation of the toxin genes. Other V. cholerae genes whose products may play a role in the pathogenicity of this organism include the toxin-coregulated pilus genes (Shaw et al., 1990, Infect. Immun. 8:3042; Sharma et al., 1989, Vaccine, 7:451;Sun et al., 1990, J. Infect. Dis. 161:1231; Hall et al., 1991, Infect. Immun. 59:2508; Taylor et al., 1987, Proc. Natl. Acad. Sci. USA 84:2833), and the gene encoding the intestinal colonalization factor (Taylor et al., 1988, Vaccine 6:151).